Selective recruitment and activation of fiber types in nerves for the control of undesirable brain state changes

ABSTRACT

We disclose methods and medical device systems for selectively recruiting a nerve fiber type within a cranial nerve, a peripheral nerve or a spinal root. Such a method may comprise applying a first pressure, a heating, and/or a cooling to a second location of the nerve, the pressure, heating, or cooling sufficient to substantially block at least one of activation or conduction in at least one fiber population through the second location of the nerve for a blocking time period; and applying an electrical signal to a first location during the blocking time period.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 14/530,964, filed Nov. 3, 2014 (published as U.S.20150051637), which is a continuation of U.S. patent application Ser.No. 13/765,795, filed Feb. 13, 2013 (issued as U.S. Pat. No. 8,880,167),the contents of each of which are hereby incorporated by reference intheir entireties.

FIELD OF THE INVENTION

This invention relates to medical device systems and methods capable ofselective recruitment, activation and/or conduction of fiber types innerves, such as cranial or, peripheral, and spinal roots.

DESCRIPTION OF THE RELATED ART

Therapies using electrical signals to provide a therapy to a patient(electro-therapy) are beneficial for certain neurological disorders,such as epilepsy and depression. Implantable medical devices (IMDs) havebeen effectively used to deliver therapeutic electrical stimulation tovarious portions of the human body (e.g., the vagus nerve) for treatingepilepsy. As used herein, “stimulation,” “neurostimulation,”“stimulation signal,” “therapeutic signal,” or “neurostimulation signal”refers to the direct or indirect application of an electrical,mechanical, thermal, magnetic, electro-magnetic, photonic, acoustic,cognitive, and/or chemical signal to an organ or a neural structure inthe patient's body. The stimulation signal is an exogenous signaldistinct from the endogenous electro-chemical or thermal activityinherent to the patient's body. In other words, the therapeuticstimulation signal (whether electrical, mechanical, thermal, magnetic,electro-magnetic, photonic, acoustic, cognitive, and/or chemical innature) applied to a cranial nerve or to other nervous tissue structurein the present disclosure is a signal applied from a medical device,e.g., a neurostimulator.

When a neurostimulation signal (whether of an electrical, mechanical,thermal, or other modality) is applied to a neural structure, energyfrom the signal enters nerve fibers within the structure. If the energyfrom the signal exceeds a threshold, the signal will cause the nervefiber to generate an action potential that may be transmitted along thelength of the nerve. Stimulation of a nerve fiber in an amountsufficient to generate an action potential is referred to herein as“recruitment” of the nerve fiber. The effect of the recruitingstimulation signal that (i.e., generation of an action potential in thefiber) is termed “activation.” Depending upon the amount of energy itcontains, the signal may recruit none, some, or nearly all of the fiberstypes within a neural structure.

Although neurostimulation has proven effective in the treatment of anumber of medical conditions, it would be desirable to further enhanceand optimize neurostimulation-based therapies to neural structures. Forexample, nerves (such as cranial nerves) typically possess multipletypes of fibers, such as myelinated (e.g., A- and B-fibers) andunmyelinated (e.g., C-fibers) with different conduction velocities thatare a function not only of the presence or absence of a myelin sheathbut also of the fibers' diameter. In general, larger diameter fibersconduct nervous impulses faster than those with smaller diameters, andimpulses travel faster in myelinated (i.e. insulated) than inunmyelinated (non-insulated) fibers.

There may be situations in which selective recruitment and/or activationof a particular fiber type or types would lead to greater efficacy or toother benefits such as reduction in the frequency or severity of adverseor deleterious effects, of a neurostimulation-based therapy. However, inthe current state of the art, selective recruitment of fiber types isperformed by adjusting the amplitude of a therapeutic electrical signal,a highly limiting approach since it does not lend to selectiverecruitment and/or activation of small diameter nerve fibers. Becausethe activation thresholds (AT) of fiber types A, B, and C can bequantitatively ordered as ATA<ATB<ATc, it is possible to administer anelectrical signal having an amplitude greater than ATA but less than ATBto selectively recruit A-fibers. Similarly, an electrical signal havingan amplitude greater than ATB but less than ATC would selectivelyrecruit A- and B-fibers. However, to recruit B-fibers, A-fibers mustalso be activated, and to recruit C-fibers, both A- and B-fibers mustalso be activated when electrical currents are delivered to the whole ofa nerve trunk. Also, if only A-fibers are desired to be recruited, anelectrical current having an amplitude greater than ATB would alsoactivate B-fibers.

Therefore, it would be desirable to have alternative techniques forselective activation of fiber types in nerves.

SUMMARY OF THE INVENTION

In some embodiments, the present disclosure relates to a method forselectively recruiting a nerve fiber type within a cranial nerve, aperipheral nerve or a spinal root, comprising applying a first pressureto a second location of said nerve, said pressure sufficient tosubstantially block at least one of activation or conduction in at leastone of an A-fiber population or a B-fiber population through said secondlocation of said nerve for a blocking time period; and applying anelectrical signal to a first location during said blocking time period.

In some embodiments, the present disclosure relates to a method forselectively recruiting a nerve fiber type of a nerve, comprisingperforming an operation selected from one of heating or cooling a secondlocation of said nerve, said heating or cooling sufficient tosubstantially block at least one of activation or conduction on at leasta first fiber type of said nerve for a blocking time period; andapplying said electrical signal to said first location during saidblocking time period.

In some embodiments, the present disclosure relates to a medical devicesystem for selectively stimulating a nerve fiber, comprising anelectrode coupled to a first location of a nerve, said electrode capableof applying an electrical signal to said first location; a nervepressure device coupled to a second location of said nerve, capable ofapplying a first pressure to the second location; a medical deviceoperatively coupled to said electrode and said nerve pressure device,said medical device comprising a controller; an electrical signalgenerator to apply an electrical signal to the first location of saidnerve using said electrode; and a pressure signal generator to applysaid first pressure to said second location of said nerve using saidnerve pressure device, to substantially block at least one of activationor conduction in at least one of an A-fiber population or a B-fiberpopulation at said second location of said nerve.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention may be understood by reference to the followingdescription taken in conjunction with the accompanying drawings, inwhich like reference numerals identify like elements, and in which:

FIG. 1A provides a stylized diagram of a medical device system implantedinto a patient's body, in accordance with one illustrative embodiment ofthe present disclosure;

FIG. 1B provides a stylized diagram of another medical device systemimplanted into a patient's body, in accordance with one illustrativeembodiment of the present disclosure;

FIG. 2A provides a block diagram of a medical device, in accordance withone illustrative embodiment of the present disclosure;

FIG. 2B provides a block diagram of a medical device, in accordance withone illustrative embodiment of the present disclosure;

FIG. 3 provides a flowchart of a method for selectively recruitingand/or activating a fiber type, in accordance with one illustrativeembodiment of the present disclosure;

FIG. 4 provides a flowchart of another method of selectively recruitingand/or activating a fiber type, in accordance with one illustrativeembodiment of the present disclosure;

FIG. 5 provides a flowchart of a method for selectively recruitingand/or activating a fiber type, in accordance with one illustrativeembodiment of the present disclosure;

FIG. 6A shows an example of vagus nerve compound action potential (CAP)showing A fiber action potentials, in accordance with one illustrativeembodiment of the present disclosure;

FIG. 6B shows an example of vagus nerve compound action potential (CAP)showing A, B, and C fiber action potentials, on a longer timescale thanthat shown in FIG. 6A, in accordance with one illustrative embodiment ofthe present disclosure;

FIG. 6C shows an example of blocking of activation/conduction on Afibers of a vagus nerve, in accordance with one illustrative embodimentof the present disclosure;

FIG. 6D shows an example of blocking of activation/conduction on A, B,and C fibers of a vagus nerve, in accordance with one illustrativeembodiment of the present disclosure;

FIG. 7 shows step responses of the temperature of a cervical vagus nervein a rabbit in response to in vivo local nerve cooling, in accordancewith one illustrative embodiment of the present disclosure;

FIG. 8 shows an example of conduction blocking of A fibers in a rabbitvagus nerve in response to local nerve cooling, in accordance with oneillustrative embodiment of the present disclosure; and

FIG. 9 shows an effect of local heating on conduction in A, B, and Cfibers in bullfrog sciatic nerves, in accordance with one illustrativeembodiment of the present disclosure.

While the disclosure is susceptible to various modifications andalternative forms, specific embodiments thereof have been shown by wayof example in the drawings and are herein described in detail. It shouldbe understood, however, that the description herein of specificembodiments is not intended to limit the invention to the particularforms disclosed, but on the contrary, the intention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the invention as defined by the appended claims.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

Illustrative embodiments of the disclosure are described herein. Forclarity, not all features of an actual implementation are described. Inthe development of any actual embodiment, numerousimplementation-specific decisions must be made to achievedesign-specific goals, which will vary from one implementation toanother. Such a development effort, while possibly complex andtime-consuming, would nevertheless be a routine undertaking for personsof ordinary skill in the art having the benefit of this disclosure.

This document does not intend to distinguish between components thatdiffer in name but not function. In the discussion and claims, the terms“including” and “includes” are used in an open-ended fashion, and shouldbe interpreted to mean “including, but not limited to.” The term“couple” or “couples” is intended to mean either a direct or an indirectelectrical connection. “Direct contact,” “direct attachment,” orproviding a “direct coupling” indicates that a surface of a firstelement contacts the surface of a second element with no substantialattenuating medium there between. The presence of small quantities ofsubstances, such as bodily fluids, that do not substantially attenuateelectrical connections does not vitiate direct contact. The word “or” isused in the inclusive sense (i.e., “and/or”) unless a specific use tothe contrary is explicitly stated.

The term “electrode” or “electrodes” described herein may refer to oneor more stimulation electrodes (i.e., electrodes for delivering atherapeutic signal generated by an IMD to a tissue), sensing electrodes(i.e., electrodes for sensing a physiological indication of a state of apatient's body), and/or electrodes that are capable of delivering atherapeutic signal, as well as performing a sensing function.

Embodiments of the present disclosure provide improved therapies fortreating medical conditions by selective recruitment of different typesof nerve fibers. As previously noted, different types of nerve fibers(e.g., the A, B, and C major fiber types, including their varioussub-types such as Aα, Aβ, Aγ, Aδ) have different activation and/orconduction thresholds for induction of action potentials therein and/orfor allowing continued conduction of action potentials along the fiber.A principal difficulty in prior attempts to provide “fiber-typespecific” neural stimulation (including particularly electricalneurostimulation) is the difficulty of selectively recruiting fibershaving a higher activation or conduction threshold (e.g., C fibers)without also recruiting fibers having a lower activation threshold(e.g., A and B fibers and sub-types thereof). The nerve fiberclassification/nomenclature used in this disclosure was proposed byErlanger and Gasser; there is also a numerical classification [Ia (Aα),Ib (Aα), II (Aβ), III (Aδ), IV (C fibers)] that is listed here in thespirit of full disclosure.

Selective activation of nerve fibers may have different effects on atarget structure (e.g., brain nuclei or cortex) from those obtained whenthe entire nerve trunk (and thus all fiber types) are activated. Forexample, activation of large myelinated fibers has a different effectupon cortical rhythms than activation of small fibers. This differencemay be exploited, for example, in treating diseases associated with orcaused by disturbed/abnormal cortical rhythms, such as epilepsy or whenblockage of conduction of nerve impulses along certain fiber types iswarranted such as in the treatment of pain.

Recruitment of fiber types in a cranial or peripheral nerve or in aspinal root, may be also accomplished through the placement of smallelectrodes inside the nerve (i.e., beneath the epineurium orintra-fascicularly) and in close proximity to the targeted fiber-typebundle(s). This is possible given the histologic organization of fibertypes in bundles or “clusters”. Localization of bundles may be performedusing one or more of: a) high resolution electrode arrays andspatio-temporal analyses of evoked nerve activity usingelectro-physiological tools (e.g., neurogram) and, when necessary,statistical/mathematical methods, b) static and/or functional imagingsuch as that made possible by certain MR modalities, near-infra redspectroscopy, etc., or c) the patient's perception of sensationselicited by stimulation (or micro-stimulation) of fiber bundles. Forexample, if the patient reports a sensation of discomfort or pain, itmay be deduced that very thinly myelinated or unmyelinated smalldiameter fibers are being activated by said stimulation.

The present disclosure provides methods and devices that temporarilyalter the activation and/or conduction threshold(s) of one of more fibertypes relative to other fiber types. This may facilitate selectiverecruitment of particular fiber types by blocking electrical conductionon particular fibers through a first location of a nerve and/or actionpotential activation of particular fibers at a second location of thenerve. In one embodiment, the thresholds of fibers having loweractivation/conduction thresholds is temporarily increased relative tothe threshold of fibers with higher thresholds. This may be done bystimulating the lower-threshold fibers (e.g., A fibers) with a differentmode or type of stimulation to temporarily alter (e.g., raise) thethreshold of the lower-threshold fibers relative to the naturally higherthreshold fibers. For example, the activation/conduction threshold for afirst fiber type and a first stimulation modality (e.g., the thresholdfor A fibers with an electrical stimulation) may be temporarily alteredrelative to that of a second fiber (e.g., the threshold of C fibers withan electrical stimulation) by providing a second stimulation modality(e.g., a mechanical stimulation such as pressure) to a neural structurehaving both the low-threshold and high-threshold fiber types. Theactivation threshold for the low-threshold fibers (e.g., A fibers) maybe temporarily increased relative to the high-threshold fibers (e.g., Cfibers) such that when the first stimulation modality (e.g., electricalstimulation) is provided to the neural structure in close temporalproximity (e.g., simultaneously or during a refractory period) to thesecond stimulation modality, the higher-threshold fibers may bepreferentially or selectively recruited relative to the lower-thresholdfibers.

In this disclosure a distinction is made between fiber activation andconduction of an action potential. That is, a fiber may be activated inthat an action potential is generated in the vicinity of the stimulussite, but not conducted/propagated beyond it, due to blockage of asegment or segment(s) of the activated fiber.

Selective recruitment or activation of nerve fibers may be performed inone of two ways: 1. activation of only certain fiber types, and 2.activation of all fiber types in a nerve trunk, and blockage ofconduction along certain fibers. The first case (activating only certainfiber types) may occur when low amplitude, high frequency electricalcurrents are delivered to a nerve trunk containing A, B and C fibertypes. In this case to the bio-physical properties of the fibers, onlyor mainly A fibers are activated. However, given the inherentdifferences in action potential thresholds among fiber types, (C fibersthreshold>B fibers threshold>A fibers threshold), it is not usuallypossible using electrical currents to activate C fibers withoutco-activating B and A fibers. In this case, selectiverecruitment/activation of fibers is accomplished via blockage ofpropagation of action potentials along certain fiber types. For example,selective recruitment of C-fibers is performed through activation of allfiber types (A, B & C) within a nerve, and blockage of conduction viacooling of or pressure on the nerve of A & B fibers.

As used herein, “selective recruitment” and “preferential recruitment”refer to increasing the fraction of higher-threshold fibers that areactivated (e.g., by creating an action potential therein) and/ordecreasing the fraction of lower-threshold fibers that are activated, bya first stimulation modality such as an electrical signal applied to theneural structure. In one embodiment, the term selective recruitment isapplied to the nerve fiber type having the higher innate or native(i.e., unaltered) activation/conduction threshold (e.g. C fibers). Theterm “modify conduction” refers to one or more of dampening,attenuating, slowing, reducing or blocking impulse conduction (e.g., theinduction and movement of an action potential) on a nerve fiber type. Inone embodiment, “modify conduction” is applied to the fiber type havingthe lower native threshold (e.g., A fibers), and whose threshold israised by the second stimulation modality (e.g., increased positivepressure). It will be appreciated, however, that the terms are related,and together refer to the effects of first and second stimulationmodalities applied to a nerve structure having two or more oflow-threshold (A), intermediate (B) and high-threshold (C) fiberstherein. The terms do not imply that no fibers of the low-threshold type(i.e., the fibers whose threshold is temporarily altered or whoseconduction is modified) are recruited or activated, although in someembodiments action potentials may be generated only in thehigh-threshold fibers. Instead, “selective recruitment” and/or “modifiedconduction” may together involve recruiting a higher fraction of thehigh-threshold fibers relative to the low-threshold fibers than would bethe case if only the first stimulation modality were applied without thesecond stimulation modality. In the example previously discussed, ahigher fraction of C fibers in a nerve structure may be activated byelectrical stimulation (relative to the fraction of A fibers and/or Bfibers) when the electrical stimulation signal is provided in closetemporal proximity to mechanical stimulation of the nervestructure—either while the mechanical stimulation is being provided, orduring a refractory period shortly thereafter in which the threshold(s)of the A and/or B fibers remain elevated relative to their thresholdswithout the presence of the second stimulation modality.

As previously noted, selective recruitment of particular types of nervefibers may be used to provide enhanced or different effects on one ormore end-target structures (e.g., brain nuclei or cortex) from thoseobtained when the entire nerve structure (and thus all fiber types) isstimulated using only a single stimulation modality (e.g., onlyelectrical stimulation). Where only one type of stimulation modality isemployed, fibers are recruited according to their unaltered thresholds,and thus effects attributable to the action of higher-threshold fibers(e.g., C-fibers) in end-target structures such as brain nuclei may beundesirably small or reflect the “mixture” of action potentials withdifferent conduction velocities and amplitudes traveling along thevarious fiber types leading to spatio-temporal dispersion. Conversely,undesired effects attributable to lower-threshold fibers may beundesirably large. Embodiments of the present disclosure may be employedto provide improved therapeutic outcomes and/or minimized adverse sideeffects.

Several stimulation modalities applied alone or in any possiblecombination, temporal sequence and parameters (e.g., intensity, durationof stimulation, waveform, rate of delivery, etc.) may be used forselectively recruiting fiber types in a cranial nerve, a peripheralnerve or a spinal root, including: 1. mechanical stimulation (e.g.,changes in pressure in reference to that normally acting on the body);2. thermal stimulation (e.g., changes in temperature in reference tonormal body temperature); 3. electrical stimulation, either asalternating or direct current and at either high frequencies (definedherein as at no less than 1 KHz) or low frequencies (defined herein asno greater than 100 Hz) of adequate pulse width, pulse shape, intensityand duration; 4. chemical stimulation (e.g., local anesthetics such aslidocaine; ions such as Ca++, Mg++ or KCl, etc.); 5. application ofstimuli to skin, muscle or tendon receptors capable of naturallyactivating specific fiber types; for example noxious stimuli such asheat or pinprick may be delivered to the ears' conchae to activate verythinly myelinated or unmyelinated (e.g., C fibers) small diameter vagalfibers.

Other strategies (e.g., exploitation of anatomo-histological properties)may be employed to selectively activate certain fibers types: abdominalvagi nerves are composed almost entirely of unmyelinated fibers.Stimulation of these segments of the vagus may be performed whenever theclinical case calls for selective activation of C fibers. The superiorlaryngeal branch of the vagus nerve, contains 70% of unmyelinatedfibers. Stimulation of this nerve using, for example, intra-fascicularelectrodes would increase the probability of selective activation of Cfibers, given they occupy most of the cross section of this branch.

In a particular example, application of sufficient pressure to a firstlocation on a nerve structure (e.g., a cervical portion of a vagusnerve) having A-, B-, and C-fibers may reduce the ability of A-fibers(or both A- and B-fibers) to conduct action potentials, and/or raise thethreshold necessary for an electrical signal to induce action potentialsin A and/or B-fibers, at the first location. Therefore, if an electricalsignal is applied to a second location on the nerve structure, whereinthe electrical currents would—absent the pressure applied to the firstlocation—elicit action potentials in A-, B-, and C-fibers, conduction ofsuch action potentials on the A-fibers or the A- and B-fibers may beblocked at the second location, while conduction of such actionpotentials on B- and C-fibers or C-fibers alone, may proceed through thesecond location. In other words, the medical device system 100 may beused to selectively recruit C-fibers or B- and C-fibers in the nerve.

The amount of pressure sufficient to block action potential conductionof A-fibers, A- and B-fibers, or A-, B-, and C-fibers may be determinedas a routine matter by persons of skill in the art having the benefit ofthe present disclosure. For example, the amount of pressure may bedetermined by recording a neurogram relating to conduction through thesecond location of the nerve; and determining a first pressure thresholdrequired to block or substantially reduce conduction along at least oneof an A fiber population or a B fiber population(s) based upon theneurogram. The pressure (or temperature, chemical or other stimulationmodality) changes required to recruit a certain fiber type, may be alsodetermined based on the effect on the organism of stimulation of thenerve. Simultaneous recording of the action potentials triggered bystimulation and of other body signals (e.g. EKG, ECoG, voiceproperties/quality/vocal cord contractions, gastrogram, etc.) allowscorrelation of the change in body signal with fiber group activity;attenuation or disappearance of changes in a body signal correlated withactivation of a certain fiber type, is indicative of blocked conductionalong said fibers.

In certain embodiments of this disclosure, alteration of electricalactivation and/or electrical conduction thresholds may be accomplishedby applying mechanical, thermal or chemical stimulation. More generally,a second stimulation modality may be used to alter one or more ofactivation or conduction thresholds associated with a first stimulationmodality, where the first and second modalities of stimulation areselected from electrical, mechanical, thermal, chemical, magnetic, andoptical stimulation modalities.

In another embodiment, A and/or B type fibers may be selectivelyrecruited and activated by either exploiting their innately highsensitivity or responsivity to low intensity, low frequency exogenouselectrical currents or by other mechanical, thermal or chemical means.

While increased positive focal or segmental positive pressure ordecreased temperature to selectively recruit fibers may be used in mostembodiments, negative pressure (e.g., partial or complete vacuum) orincreased temperature may be also utilized. All means to selectivelyrecruit nerve fibers may be applied to neural structures, so long ascare is exercised to protect their integrity.

While delivery of electrical currents may be the preferred stimuli foractivation of recruited fibers, chemical, mechanical, thermal andoptical/photonic stimuli may be also used in any combination.

Turning to FIG. 1A, a medical device system 100 according to oneembodiment of the present disclosure is schematically depicted. Themedical device system 100 may comprise an electrode 110 coupled to afirst location of a nerve 105. The electrode 110 may be capable ofapplying an electrical signal to the first location of the nerve 105.

The nerve 105 may be any anatomical neural structure, such as a cranialnerve, a peripheral nerve, or a spinal root. In one embodiment, thenerve is a vagus nerve (cranial nerve X). Generally, the nerve 105 willcomprise one or more fiber types, which may include myelinated andunmyelinated fibers. For many nerves, and especially for cranial nerves,the myelinated fibers include A-fibers and B-fibers, and theunmyelinated fibers include C-fibers.

The electrode 110 may be selected from any electrode known in the artfor use in electrically stimulating nerves, including cranial nerves,peripheral nerves, or spinal roots. In a particular embodiment, theelectrode 110 may be a helical circumneural electrode, such as theelectrodes incorporated into the PerenniaFlex lead/electrode system,produced by Cyberonics, Inc., Houston, Tex. The electrode 110 may beconfigured to deliver an electrical stimulation therapy to the nerve 105(e.g., a vagus nerve) treat a medical condition, such as epilepsy,depression, or a cardiovascular disorder. Other electrodes known in theart, such as cuff electrodes, paddle electrodes, needle electrodes, wireelectrodes, etc., may be used in addition to or instead of helicalelectrodes. Electrodes may be placed on the epineurium or beneath it(e.g., in the perineurium and/or endoneurium or in the structurescontained within these membranes (intra-fascicular electrodes).

The medical device system 100 may also comprise a nerve pressuredelivery device (NPD) 120, such as a pressure delivery cuff as shown inFIG. 1A, coupled to a second location of the nerve 105. NPD 120 may becapable of applying a first pressure to the second location of the nerve105. In one embodiment, NPD 120 may be capable of applying a pluralityof pressures to the second location. In one embodiment, NPD 120 maycomprise a clamp or other device that continuously applies a firstpressure to the nerve. However, such an embodiment is not preferredbecause it may provide an elevated risk of damage to the nerve or mayalter the overall function of the nerve by permanently changing thefunction of one or more nerve fiber types.

In one embodiment, NPD 120 may be capable of providing a variable rangeof pressures to the nerve 105, which may include any pressure up to amaximum pressure that may be safely applied to the nerve without causingdamage. In some embodiments, NPD 120 may be capable of providing acontinuously variable pressure, while in other embodiments it may becapable of providing one or more programmed pressures to the secondlocation. In one embodiment, pressure is provided to the nerve only inclose temporal proximity to an electrical signal that is applied to thenerve; otherwise, pressure is not applied to the nerve.

In one embodiment, NPD 120 may be capable of providing a first pressureto a second location of the nerve 105 for a blocking time period, duringwhich one or more of the activation threshold and/or conductionthresholds for at least one nerve fiber type in the nerve 105 isaltered. NPD 120 may be capable of not providing pressure to the nerveduring a non-blocking time period. In a particular embodiment, NPD 120may provide a first pressure to the second location of nerve 105 whilean electrical signal is applied to the nerve at the first location, andnot provide a pressure to nerve 105 when the electrical signal is notapplied to the nerve. Such an approach may minimize the risk ofmechanically induced damage to, or altered function of, nerve 105. Inone embodiment, the manner and modes by which pressure is applied tonerve 105 by NPD 120 may be programmed by a user from a programmingdevice. NPD 120 may apply positive or negative pressure to nerve 105.

In some embodiments, electrode 110 and NPD 120 may comprise separatedevices at different first and second locations, as shown in FIG. 1A. Inone embodiment (not shown in FIG. 1A), electrode 110 and NPD 120 may bepart of an integrated device including both an electrode 110 and an NPD120, and capable of applying both an electrical signal and a pressure toa single physical location on the nerve that comprises both the firstand second locations.

Referring again to FIG. 1A, pressure may be applied to the nerve 105from NPD 120 in a number of different ways, such as by pumping a fluid(e.g., a gas or a liquid) into a cuff as shown in FIG. 1A, by alteringthe temperature of a shape memory material (e.g., heating or cooling acircumneural nitinol ring), by applying an electrical current to apiezoelectric material, by use of a spring element, or by use of a wormgear to drive a clamp mechanism, among other techniques.

Although FIG. 1A depicts NPD 120 as being circumneural, in otherembodiments, NPD 120 may be configured for deployment in otherorientations relative to the second location of the nerve 105. In oneembodiment, NPD 120 may be C-shaped or cover only a portion of theperiphery of the nerve. In another embodiment, NPD 120 may beintra-neurally (intra-fascicular) placed.

The first location (to which the electrode 110 is coupled) and thesecond location (to which NPD 120 is coupled) may be in any orientation.However, in embodiments in which electrode 110 and NPD 120 compriseseparate structural elements (as shown in FIG. 1A), the selectiveblocking of action potential conduction provided by operation of NPD 120is only effective with regard to action potentials propagating fromelectrode 110 in the direction of NPD 120. Therefore, if the electricalsignal applied at 110 is applied as a therapy for a condition in thebrain (e.g., epilepsy), NPD 120 should be proximal to the brain relativeto electrode 110. Similarly, if the electrical signal applied at 110 isapplied as a therapy for heart disease (e.g., congestive heart failure),or to block vagal nerve impulses traveling for example towards theheart, NPD 120 should be proximal to this organ relative to electrode110. More generally, for an end-target organ or body structure for whichselective recruitment of action potentials is desired, NPD 120 should beproximal to the organ relative to electrode 110. For embodiments havinga unitary electrode and NPD acting at a single physical location on thenerve, the selective recruitment may be effected by altering only theactivation threshold of the target nerve type(s), since the issue ofconduction does not apply.

Referring again to FIG. 1A, the medical device system 100 may alsocomprise a medical device 130 operatively coupled to the electrode 110and NPD 120. The medical device 130 may be configured to direct NPD 120to apply a first pressure to the second location of nerve 105. In oneembodiment, the first pressure is sufficient to substantially modifyactivation or conduction thresholds on at least one of an A-fiberpopulation or B-fiber population of the nerve at the second location fora blocking time period. Medical device 130 may also be configured todirect the electrode 110 to apply an electrical signal to the firstlocation of the nerve 105 during the blocking time period. In oneembodiment, the medical device 130 may be configured to direct the NPD120 to cease applying the first pressure to the second location afterthe blocking time period has elapsed. This may be done to avoid damageto the nerve that may be associated with applying pressure to the nervefor extended time periods. More than one NPD 120 may be placed in thesame nerve as needed for the clinical application at hand.

Turning to FIG. 1B, another embodiment of a medical device system 100 isdepicted. Many elements of FIG. 1B are the same as in FIG. 1A, includingnerve 105 and electrode 110, and will not be discussed further. Themedical device system 100 may comprise a thermal manipulation unit (TMU)140 coupled to a second location of the nerve 105 capable of heating orcooling the second location of the nerve 105. The TMU 140 may be aPeltier device, or one capable or circulating a coolant/refrigerant or aheating fluid, among other heating and cooling apparatus and techniques.Heating or cooling of the nerve using TMU 140 may be controlled by amedical device 150 to prevent exposure of nerve 105 to temperatures thatmay damage it or alter its function for periods of times longer thanthose required for blockage of conduction of impulses along certainfiber types. The duration of cooling or heating will also controlled tominimize risk of nerve damage or prolonged (for the task at hand)dysfunction. Safety limits may be set to minimize one or both of thetemperature to which the second location of the nerve may be heated orcooled, as well as the time of such heating or cooling.

In one embodiment, TMU 140 may heat or cool only a portion of theperiphery of the nerve, as shown in FIG. 1B. In other embodiments, TMU140 may be completely circumneural, or may involve a plurality ofindependently operable elements to heat and cool particular portions ofthe periphery of the nerve. The TMU 140 may be endowed with probes thatmay be safely placed inside a nerve to cool down or heat up certainfiber bundles or fascicles.

Regardless of the particular configuration of TMU 140, medical device150 may be configured to direct the thermal manipulation unit 140 toheat and/or cool the second location of nerve 105, wherein the heatingand/or cooling is sufficient to substantially modify activation and/orconduction threshold(s) on at least one fiber population at the secondlocation of nerve 105 for a blocking time period.

In one embodiment, cooling the nerve 105 at the second location maysubstantially modify conduction of an A-fiber population or B-fiberpopulation for a blocking time period. Medical device 150 may further beconfigured to direct electrode 110 to apply an electrical signal to thefirst location of the nerve 105 during the blocking time period.

Without being bound by theory, cooling a nerve comprising A-, B-, andC-fibers may be employed at a second location using TMU 140 to reducethe ability of A-fibers, or both A- and B-fibers to conduct actionpotentials at the second location. Therefore, if an electrical signal isapplied to a first location of nerve 105 using electrode 110, whereinthe electrical signal is sufficient to induce action potentials in A-,B-, and C-fibers, conduction of such action potentials on the A-fibersor the A- and B-fibers may be blocked at the second location of thenerve, while conduction of such action potentials on B- and C-fibers, orC-fibers alone, may proceed through the cooled portion of the nerve. Inother words, the medical device system 100 may be used to selectivelyrecruit C-fibers or B- and C-fibers in the nerve.

Without being bound by theory, heating a nerve 105 comprising A-, B-,and C-fibers may be employed at a second location using TMU 140 toreduce the ability of C-fibers, or both B- and C-fibers, to conductaction potentials through the heated portion of the nerve. In otherwords, TMU 140 may be used to selectively recruit A-fibers or A- andB-fibers in the nerve by heating at least a portion of the nerve at thesecond location. Although A- and/or B-fibers may also be selectiverecruited by applying an electrical signal of low energy to the nerve,with the electrical current being below the activation threshold ofC-fibers or B- and C-fibers but above that of A-fibers or A- andB-fibers, using heat to block conduction on C-fibers or B- and C-fibersallows the application of higher energy electrical signals toselectively recruit more A-fibers or A- and B-fibers than is possible atlower current intensities.

In some embodiments, the medical device system may comprise a pluralityof NPDs 120 and/or TMUs 140. For example, the medical device system maycomprise two NPDs 120 or two TMUs 140. In such embodiments, the two ormore NPDs 120 and/or TMUs 140 may be located in positions flanking theelectrode 110, such that at least one NPD 120 p and/or TMU 140 p isproximal to the brain relative to electrode 110, and at least one otherNPD 120 d and/or TMU 140 d is distal to the brain relative to electrode110. In such embodiments, activation or conduction may be differentiallyblocked in the afferent (toward the brain) and efferent (away from thebrain) directions. For example, an electrical signal delivered viaelectrode 110 to a nerve 105 in the neck of a patient may activate allof A-, B-, and C-fibers. However, it may be desirable to block efferentconduction in the direction of the heart on some or all of A-, B-, orC-fibers to minimize a reduction of heart rate that might occur ifefferent conduction on all fibers were not blocked. In the afferentdetection, however, it may be desirable to block conduction in thedirection of the brain on a different set of some or all of A-, B-, orC-fibers to produce a desired effect in the brain.

For another example, delivery of an electrical signal by electrode 110to a point on the vagus nerve that is proximal to the brain relative tothe recurring laryngeal nerve (a branch of the vagus nerve) may induceaction potentials that propagate efferently down the recurring laryngealnerve. Because the recurring laryngeal nerve innervates the vocal cordsand related anatomical structures, these induced action potentials mayreversibly impair operation of the voice, leading to a husky or whisperyvoice while the electrical signal is being delivered to the vagus nerve.Therefore, it may be desirable to use an NPD 120 d and/or a TMU 140 d toblock substantially all efferent conduction from the site of electrode110, thereby reducing any impairment of the voice. At the same time, itmay be desirable to use an NPD 120 p and/or a TMU 140 p to blocksubstantially all afferent conduction on one of more fiber types (e.g.,A- and B-fibers) from the site of electrode 110, thereby allowingselective recruitment of the unblocked fiber type(s) (e.g., C-fibers) inthe afferent direction.

In other embodiments, the medical device system may comprise a singleNPD 120 or TMU 140, such that activation or conduction of electricalsignals at or through the location of the NPD 120 or TMU 140 isdifferentially allowed depending on the direction of electrical signalpropagation. For example, it may be desirable at some times to blockefferent conduction on some or all of A-, B-, or C-fibers of endogenoussignals (generated by the brain) and/or signals delivered to the nerve105 by an electrode 110 p. It may also be desirable at different timesto block afferent conduction on a different set of some or all of A-,B-, or C-fibers of endogenous signals (generated by the viscera) and/orsignals delivered to the nerve 105 by an electrode 110 d.

In some embodiments, one or more NPDs 120 and/or TMUs 140 may be used toreversibly block all conduction or activation of action potentials inboth the afferent and efferent direction. Such a blocking is comparableto a vagotomy (surgical severance of the vagus nerve), but with theadvantage that such blocking is reversible when implemented by NPDs 120and/or TMUs 140, in contrast with surgical blocking, which isirreversible. In yet another embodiment. the NPD 120 and TMU 140 may beplaced side by side proximally or distally to the brain or heart. Inanother embodiment, the NPD 120 and TMU 140 may integrated into a singleunit/device.

FIG. 2A presents a block diagram of a medical device 130 as shown inFIG. 1A. Medical device 130 may comprise a sensor 210 to receive atleast one physiological data stream. The physiological data stream(s)may comprise autonomic data, such as cardiac data (e.g., heart rate,heart rate variability), respiratory data (e.g., breathing rate, tidalvolume), skin resistivity, muscle activity, or eye movement, amongothers. Alternatively or in addition, the physiological data stream maycomprise neurologic data, such as body movement data, responsivenessdata, awareness data, EEG or ECoG, among others. The physiological datastream may comprise other types of physiological data. More informationregarding physiological data streams and sensors suitable to receivethem is provided by U.S. patent application Ser. No. 12/896,525, filedOct. 1, 2010, which is incorporated herein by reference. Although notdepicted in FIG. 2A, medical device 130 may also comprise hardwareand/or software for conditioning and processing the physiological datastream(s), e.g., sense-amps, pre-filters, filters, A/D and/or D/Aconverters, memory, etc.

Medical device 130 may also comprise a controller 220 to directoperations of one or more other units of medical device 130 or medicaldevice system 100. In one embodiment, the controller 220 may determine atype and/or parameters of the electrical signal to be applied to thefirst location of the nerve 105. The parameters of the electrical signalmay include pulse amplitude, frequency, pulse width, on-time, off-time,waveform shape, inter-stimulus interval which may be uniform orvariable, duty cycle, the timing of signal application, or two or morethereof, among others, and may be stored in a memory of the device (notshown).

Controller 220 may further control one or more pressures to be appliedthrough the NPD 120 to the nerve 105. The controller 220 may control themagnitude of the pressure, the duration of the pressure, and the time atwhich the pressure is applied, and changes (including rates of change)in the pressure applied to the nerve 105 through NPD 120. In thismanner, controller 220 may be used to substantially block actionpotential activation and/or conduction on A-fibers alone, on A- andB-fibers, or on all of A-, B-, and C-fibers. In some embodiments, thecontroller 220 may select which fiber type(s) to selectively recruit,based on information received from sensor 210 and/or other sources (adevice memory (not shown), an input from a patient, caregiver, orphysician, etc.).

Medical device 130 may also comprise an electrical signal generator 230configured to apply an electrical signal to the first location of thenerve 105 using electrode 110. In some embodiments, one or moreparameters of the electrical signal from electrical signal generator 230may be based upon the physiological data stream sensed by sensor 210.

Medical device 130 may also comprise a pressure signal generator 240configured to apply the first pressure to the second location of thenerve 105 using NPD 120 to substantially block conduction on at leastone of an A-fiber population or a B-fiber population of the secondlocation of the nerve.

FIG. 2B presents a block diagram of the medical device 150 as shown inFIG. 1B. Medical device 150 may comprise a sensor 210, controller 220,and electrical signal generator 230, generally as described above withreference to FIG. 2A. In some embodiments wherein the medical devicesystem 100 comprises both a cooling unit and a heating unit, thecontroller 220 may determine a fiber-type population of the portion ofthe nerve 105 for selective recruitment, based on data received frombody sensors or from a user.

Medical device 150 may also comprise a cooling unit 250 configured tocool the second location of the nerve using TMU 140 to substantiallyblock conduction on at least one of a A-fiber population or a B-fiberpopulation at the second location of the nerve 105. The cooling unit 250may be configured to cool the second location by issuing instructions toTMU 140. Medical device 150 may also comprise a heating unit 260configured to heat the second location of the nerve using TMU 140 tosubstantially block conduction on at least one of a B-fiber populationor a C-fiber population of the second location of the nerve. The heatingunit 260 may be configured to heat nerve 105 by issuing instructions toTMU 140.

FIG. 3 presents a flowchart depiction of a method according to oneembodiment of the present disclosure. In the method, a nerve fiber typewithin a nerve, such as a cranial nerve or a peripheral nerve, may beselectively recruited by receiving at 310 a prompt to apply anelectrical signal to a first location of the nerve. The prompt may beissued by hardware, software, and/or firmware in a medical device system100; by a patient, a caregiver, or a medical professional; or by anothersource, and may be received by appropriate hardware, software, and/orfirmware in a medical device system 100.

The method may further comprise applying at 320 a first pressure to asecond location of the nerve, wherein the pressure is sufficient tosubstantially block activation and/or conduction on at least one of anA-fiber population or a B-fiber population through the second locationof the nerve for a blocking time period.

In addition, the method may further comprise applying at 330 anelectrical signal to the first location during the blocking time period.In some embodiments, application of the first pressure to the secondlocation may be discontinued after the application of the electricalsignal.

FIG. 4 presents a flowchart depiction of a method according to anotherembodiment of the present disclosure. In this method, receiving a promptat 410 and applying an electrical signal at 430 may be as describedabove with reference to steps 310 and 330 in FIG. 3.

The method depicted in FIG. 4 may further comprise cooling the nerve ata second location of the nerve at 420, wherein the cooling is sufficientto substantially block activation and/or conduction on at least one ofan A-fiber population or a B-fiber population at the second location fora blocking time period.

Although the use of pressure and the use of thermal manipulation havebeen separately described as techniques of blocking action potentialconduction in particular fiber types of nerves, they may be usedtogether. In other words, a medical device system 100 may comprise botha NPD 120 and a TMU 140, with appropriate controlling hardware,software, and/or firmware for the use of both, and the methods depictedin FIGS. 3 and 4 may be performed simultaneously or contemporaneously.

In a further embodiment, receiving a prompt to selectively recruit anerve fiber type within a nerve 105 may be implemented using a neurogramto measure compound action potentials on the nerve. Pressures and/ortemperatures (or heating/cooling rates) at which selective nerve fibertypes are blocked within the nerve may be determined manually or by anautomated program that incrementally changes one or both of pressure andtemperature provided by NPD 120 and TMU 140. This may be done, e.g., byapplying a particular pressure and/or temperature (or heating/coolingrate) to the nerve, applying an electrical signal to the nerve duringapplication of the pressure/temperature, and measuring the compoundaction potential of the nerve induced by the electrical signal. Thecompound action potential may be analyzed to determine A-fiber, B-fiber,and C-fiber components, and the results may be compared to otherneurograms in which no blocking pressure/temperature is applied to thenerve to determine which fiber types have been blocked, and themagnitude of the blocking effect. The pressure, thermal or chemical(dose/concentration) parameters required for blockage may then be storedin memory for later use (e.g., by a physician). Since nerve fiberexcitability is non-stationary (i.e., it is multi-factorially determinedand the factors vary as a function of time or state), the effectiveparameters for blocking may also vary. Differences in blockingparameters, if any, for a variety of electrical signals may be stored inmemory with all relevant temporal (e.g., time of day) and the stateinformation. The data necessary for pressure and/or thermal blockage ofcertain fiber types for each of a number of different electrical signalsmay be stored in, e.g., a lookup table for use by a medical device toachieve a desired level of blockage. An automated program may beemployed to periodically regenerate the data as the patient's conditionchanges.

Adjustments to blocking pressure and/or temperatures may be implementedautomatically or manually, either using the stored neurogram settings oractual (real-time) neurogram information recorded during electricalstimulation. In addition to adjustments made to the pressure and/ortemperature settings made from neurogram information, adjustments tothese values may also be made from therapeutic efficacy determinationsor adverse event determinations from sensed body data (e.g., heart rate,skin resistivity, respiratory rate, tidal volume, blood pressure, EEG,ECoG, cognitive data, kinetic data, etc.) after the recruited nervefibers are activated using electrical or some other stimulation modality(e.g., chemical). More generally, pressure and/ortemperature/heating/cooling and/or electrical settings may be adjustedor optimized based on therapeutic efficacy or adverse events.

The foregoing process for identifying pressure, temperature or chemicalsettings to achieve particular fiber recruitment levels may beautomated. In particular, a program may be implemented in whichappropriate pressure and temperature settings, are determined based uponthe output of the neurogram. The pressures, temperatures and chemicals(type and dose/concentration) at which selective fiber types are blockedto a desired level may be identified and then stored memory. In oneembodiment, electrical stimulation may be enabled only when theeffective (for the task at hand) blocking pressures, temperatures and/ordose/concentration of chemicals are reached. Adjustments to pressure,temperature and type of chemical, concentration/dose may be made inreal-time using the neurogram or other measured effects of the therapy.Blocking pressures, temperatures or concentration/dose may be determinedbased on the therapeutic efficacy, or by the presence of adverse effectscaused by said blocking modalities. The effect of selective activationof fibers may be determined based on autonomic, neurologic, metabolic orother signals, and used to determine the optimal temperature, pressureor type of chemical and concentration applied to a nerve. As usedherein, “optimal” or “optimized” may refer to parameters providing animprovement in response relative to other outcomes.

Turning to FIG. 5, a flowchart depiction of a method 500 according tosome embodiments of the present disclosure is shown. Method 500comprises acquiring and analyzing at 510 at least one biological signal.The analysis at 510 may reveal a state change in one or more tissues,organs, or organ systems of a patient, e.g., an epileptic event in thebrain of a patient, among other possibilities. If a state change is notdetected at 520, flow returns to acquiring and analyzing at 510. If astate change is detected at 520, the method may comprise selectivelyrecruiting at 530 one or more nerve fiber populations in a nerve ofinterest, such as a cranial nerve, a peripheral nerve, or a spinal root.Selective recruiting at 530 may allow later stimulation of a desirednerve fiber population to prevent, abort, or minimize the intensity of,i.e., treat, the state change. The biological signals may beneurological (cognitive, kinetic, EEG, ECOG, chemical, thermal,mechanical), autonomic (EKG, blood pressure, respirations, skinresistance; catecholamine concentrations or their metabolites),endocrine (cortisol, prolactine) metabolic (pH, glucose) or markers oftissue stress (lactic acid, CK, free radicals etc.). More information onsuch signals and their detection may be found in U.S. Pat. No.8,337,404, issued Dec. 25, 2012; U.S. patent application Ser. No.13/098,262, filed Apr. 29, 2011; and U.S. patent application Ser. No.13/288,886, filed Nov. 3, 2011; all of which are hereby incorporatedherein by reference.

After selectively recruiting at 530, a determination at 540 may be madeas to whether the selective recruiting at 530 was successful. Thisdetermination at 540 may be based on a neurogram, on evoked responsesrecorded from the brain or on changes in cortical rhythms. If no,selectively recruiting at 530 may be continued or modified. If selectiverecruiting at 530 was determined at 540 to be successful, a prompt maybe issued at 550 for nerve stimulation of the selectively recruitedfiber population. Such stimulation of a desired nerve fiber populationmay prevent, abort, or minimize the intensity of, i.e., treat, the statechange.

FIGS. 6-9 generally show the effect of pressure or temperaturemodulation on blockage of activation or conduction on one or more fiberpopulations within a nerve. FIGS. 6-9 are taken from previouslypublished papers.

FIG. 6A shows an example of vagus nerve compound action potential (CAP)showing A fiber action potentials. Specifically, an electrical stimulusis delivered to a vagus nerve at the point indicated by the upwardarrow. The amplitude of the stimulus was chosen to induce actionpotentials on A fibers with minimal activation of other fiber types,i.e., the amplitude was greater than ATA and less than ATB. The localpeak immediately after delivery of the stimulus is an artifact ofstimulus. The next largest peak, about 0.75 msec after delivery of thestimulus, is an action potential propagated along A fibers. The shorterhumps seen about 1.5-5 msec after delivery of the stimulus are actionpotentials propagated along B fibers.

FIG. 6B shows an example of vagus nerve compound action potential (CAP)showing A, B, and C fibers, on a longer timescale than that shown inFIG. 6A. The delivered electrical stimulus had an amplitude sufficientto activate all three fiber types, i.e., the amplitude was greater thanATC. By expanding the scale, action potentials propagated along C fiberscan be clearly seen in the wide peak around 18 msec after delivery ofthe stimulus.

In both FIGS. 6A and 6B, activation and conduction on all fiber typeswere unblocked by pressure, temperature, or other means.

FIG. 6C shows an example of blocking of activation/conduction on A and Bfibers of a vagus nerve by cooling. Cooling was sufficient to blockactivation/conduction on A fibers (compare the first few msec afterdelivery of the stimulus in this figure with FIG. 6B), whileactivation/conduction on C fibers was unimpaired.

FIG. 6D shows an example of blocking of activation/conduction on A, B,and C fibers of a vagus nerve. In contrast to FIG. 6C, cooling wassufficient to block activation/conduction on all fiber types. As aresult, only the peak for the stimulation artifact is visible. No fibertypes were activated or conducted action potentials during roughly 50msec after stimulation delivery.

FIG. 7 shows step responses of the temperature of a cervical vagus nervein a rabbit in response to in vivo local nerve cooling. As can be seen,application of cooling to 0° C. (first vertical dashed line) cooled thenerve from body temperature to 0° C. within about 2 min. Thereafter,heating to 37° C. warmed the nerve from 0° C. to body temperature withinabout 90 sec.

FIG. 8 shows an example of rapid conduction blocking of A fibers in arabbit vagus nerve in response to local nerve cooling. FIGS. 7-8 aretaken from Patberg, et al., J. Neurosci. Methods, 10:267-275 (1984).

FIG. 9 shows an effect of local heating on conduction in A, B, and Cfibers in bullfrog sciatic nerves. As can be seen, heating to about42.8° C. reduced the amplitude of conducted action potentials in Afibers by about 50%, with further reduction observed for heating toabout 43.4° C. B fibers were the most sensitive to heating, decreasingin amplitude by about 80% before the temperature reached 30° C. anddisappearing just below 44.0° C. The C fibers were least sensitive toheating, not reaching a minimum amplitude until heated to about 44.8° C.FIG. 9 is taken from Treanor, et al., Am. J. Physiol. 175:258-262(1953).

Additional embodiments of the disclosure are described herein in thefollowing numbered paragraphs.

100. A medical device system for selectively activating a nerve fiberpopulation type, comprising:

an electrode coupled to a first location of a nerve, said electrodecapable of applying an electrical signal to said first location;

a pressure delivery device coupled to a second location of said nervecapable of applying a first pressure to said second location of saidnerve; and

a medical device operatively coupled to said electrode and said pressuredelivery device, said medical device capable of:

directing said pressure delivery device to apply a first pressure atsaid second location of said nerve, said pressure sufficient tosubstantially modify at least one of electrical activation andelectrical conduction of at least one of an A-fiber population orB-fiber population at said second location for a blocking time period;and

directing said electrode to apply said electrical signal to said firstlocation of said nerve during said blocking time period.

101. The medical device of numbered paragraph 100, wherein said medicaldevice comprises a controller configured to select a fiber-typepopulation of said portion of the cranial or peripheral nerve whoseelectrical activation or electrical conduction is modified by saidpressure delivery device.

102. The medical device system of numbered paragraph 100, wherein saidpressure delivery device is intrafascicular and has an adjustablecircumference.

103. A medical device system for selectively stimulating a nerve fiber,comprising:

an electrode coupled to a first location of a nerve, said electrodecapable of applying an electrical signal to said first location;

a thermal manipulation unit coupled to a second location of said nerve,capable of heating or cooling said nerve at said second location; and

a medical device operatively coupled to said electrode and said thermalmanipulation unit, said medical device comprising:

a controller

an electrical signal generator to apply an electrical signal to thefirst location of said nerve using said electrode; and

a thermal manipulation signal generator to heat or cool said nerve atsaid second location using said thermal manipulation unit, tosubstantially block at least one of activation or conduction in at leastone of an A-fiber population, a B-fiber population, or a C-fiberpopulation of said second location of said nerve.

104. The medical device system of numbered paragraph 103, wherein theheating or cooling of the nerve is performed using a cooling or aheating element placed on the epineurium.

105. The medical device system of numbered paragraph 103, wherein thecooling or heating element is intra-neural/intra-fascicular.

106. The medical device system of numbered paragraph 103, furthercomprising:

a nerve pressure device coupled to a third location of said nerve,capable of applying a first pressure to the third location; and

said medical device further comprising a pressure signal generator toapply said first pressure to said third location of said nerve usingsaid nerve pressure device.

107. The medical device system of numbered paragraph 103, wherein atleast one parameter defining said electrical signal is programmablyselected, said at least one parameter selected from a pulse current, apulse width, a frequency, an on-time and an off-time.

108. The medical device system of numbered paragraph 103, wherein saidthermal manipulation unit is programmably selectable for applying aplurality of temperature values and an on-time and an off-time to saidsecond location of said nerve.

109. The medical device system of numbered paragraph 103, wherein saidthermal manipulation unit is a Peltier device to cool or heat.

110. A medical device system for selectively stimulating a nerve fiber,comprising:

an electrode coupled to a first location of a nerve, said electrodecapable of applying an electrical signal to said first location;

a thermal manipulation unit coupled to a second location of said nerve,capable of heating or cooling said nerve at said second location;

a nerve pressure device coupled to a third location of said nerve,capable of applying a first pressure to the third location and

a medical device operatively coupled to said electrode, to said thermalmanipulation unit and to said nerve pressure device, said medical devicecomprising:

a controller;

an electrical signal generator to apply an electrical signal to thefirst location of said nerve using said electride;

a thermal manipulation signal generator to heat or cool said nerve atsaid second location using said thermal manipulation unit; and

a nerve pressure device capable of applying pressure at said thirdlocation to substantially block at least one of activation or conductionin at least one of an A-fiber population, a B-fiber population, or aC-fiber population of said second location of said nerve.

111. The medical device system of numbered paragraph 110, wherein thesecond and third locations are the same.

112. A method for selectively recruiting a nerve fiber type within acranial nerve, a peripheral nerve or a spinal root for treating apatient having one of epilepsy and depression, comprising:

applying an electrical signal to of said nerve, said electrical signalhaving an effect of activating only an A-fiber population.

What is claimed is:
 1. A medical device system for selectivelystimulating a nerve fiber type within a cranial nerve, a peripheralnerve or a spinal root, comprising: an electrode adapted to be coupledto a first location of a cranial nerve, a peripheral nerve or a spinalroot, the electrode capable of applying an electrical signal to at leastone of a first nerve fiber type or a second nerve fiber type at thefirst location, wherein the first nerve fiber type has a differentnative activation threshold from the second nerve fiber type; a nervepressure device adapted to be coupled to a second location of thecranial nerve, the peripheral nerve or the spinal root, the nervepressure device being capable of applying a first pressure to the secondlocation; a medical device operatively coupled to the electrode and thenerve pressure device, the medical device comprising: a controller; anelectrical signal generator configured to apply the electrical signal tothe first location of the cranial nerve, the peripheral nerve, or thespinal root using the electrode to activate at least the second nervefiber type at the first location to conduct towards the second locationand towards a target innervated structure or system; and a pressuresignal generator configured to apply the first pressure to the secondlocation of the cranial nerve, the peripheral nerve, or the spinal rootusing the nerve pressure device, the first pressure attenuatingconduction of the first nerve fiber type so that a higher fraction ofthe second nerve fiber type relative to the first nerve fiber typeconduct away from the second location towards the target innervatedstructure or system.
 2. The medical device system of claim 1, whereinthe first nerve fiber type is an A-fiber and the second nerve fiber typeis a B-fiber or a C-fiber.
 3. The medical device system of claim 1,wherein the first nerve fiber type is a myelinated fiber and the secondnerve fiber type is an unmyelinated fiber.
 4. The medical device systemof claim 1, further comprising: a sensor to receive at least one bodydata stream; wherein the electrical signal generator is adapted to applythe electrical signal to the first location of the cranial nerve, theperipheral nerve or the spinal root based upon the at least one bodydata stream.
 5. The medical device system of claim 4, wherein the secondlocation is proximal to the heart, relative to the first location, andthe electrical signal is applied as a therapy for a cardio-vascularcondition.
 6. The medical device system of claim 5, wherein the at leastone body data stream comprises sensed body data of at least one of thefollowing: EKG, blood pressure, respirations, skin resistance,catecholamine concentrations, concentrations of metabolites ofcatecholamines, autonomic signals, metabolic signals, glucose levels, orlactic acid concentrations.
 7. The medical device system of claim 1,wherein at least one parameter defining the electrical signal isprogrammably selected, the at least one parameter selected from a pulsecurrent, a pulse width, a frequency, an on-time and an off-time.
 8. Themedical device system of claim 1, wherein the nerve pressure device iscapable of applying a plurality of pressures at the second location,wherein the pressure signal generator is capable of applying theplurality of pressures to the second location using the nerve pressuredevice, and wherein the plurality of pressures are selectable.
 9. Amedical device system for selectively stimulating a nerve fiber typewithin a cranial nerve, a peripheral nerve or a spinal root, comprising:an electrode adapted to be coupled to a first location of a cranialnerve, a peripheral nerve or a spinal root, the electrode capable ofapplying an electrical signal to at least one of a first nerve fibertype or a second nerve fiber type at the first location, wherein thefirst nerve fiber type has a different native activation threshold fromthe second nerve fiber type, and wherein the first nerve fiber type isan A-fiber and the second nerve fiber type is a B-fiber or a C-fiber; anerve pressure device adapted to be coupled to a second location of thecranial nerve, the peripheral nerve or the spinal root, the nervepressure device being capable of applying a first pressure to the secondlocation; a medical device operatively coupled to the electrode and thenerve pressure device, the medical device comprising: a controller; anelectrical signal generator configured to apply the electrical signal tothe first location of the cranial nerve, the peripheral nerve, or thespinal root using the electrode to activate at least the second nervefiber type at the first location to conduct towards the second locationand towards a target innervated structure or system; and a pressuresignal generator configured to apply the first pressure to the secondlocation of the cranial nerve, the peripheral nerve, or the spinal rootusing the nerve pressure device, the first pressure attenuatingconduction of the first nerve fiber type so that a higher fraction ofthe second nerve fiber type relative to the first nerve fiber typeconduct away from the second location towards the target innervatedstructure or system.
 10. The medical device system of claim 9, whereinthe first nerve fiber type is a myelinated fiber and the second nervefiber type is an unmyelinated fiber.
 11. The medical device system ofclaim 9, wherein the second location is proximal to the heart, relativeto the first location, and the electrical signal is applied as a therapyfor a cardio-vascular condition.
 12. The medical device system of claim9, wherein the at least one body data stream comprises sensed body dataof at least one of the following: EKG, blood pressure, respirations,skin resistance, catecholamine concentrations, concentrations ofmetabolites of catecholamines, autonomic signals, metabolic signals,glucose levels, or lactic acid concentrations.
 13. The medical devicesystem of claim 9, wherein at least one parameter defining theelectrical signal is programmably selected, the at least one parameterselected from a pulse current, a pulse width, a frequency, an on-timeand an off-time.
 14. The medical device system of claim 9, wherein thenerve pressure device is capable of applying a plurality of pressures atthe second location, wherein the pressure signal generator is capable ofapplying the plurality of pressures to the second location using thenerve pressure device, and wherein the plurality of pressures areselectable.
 15. A medical device system for selectively stimulating anerve fiber type within a cranial nerve, a peripheral nerve or a spinalroot, comprising: an electrode adapted to be coupled to a first locationof a cranial nerve, a peripheral nerve or a spinal root, the electrodecapable of applying an electrical signal to at least one of a firstnerve fiber type or a second nerve fiber type at the first location,wherein the first nerve fiber type has a different native activationthreshold from the second nerve fiber type, the first nerve fiber typebeing a myelinated fiber and the second nerve fiber type being anunmyelinated fiber; a nerve pressure device adapted to be coupled to asecond location of the cranial nerve, the peripheral nerve or the spinalroot, the nerve pressure device being capable of applying a firstpressure to the second location; a medical device operatively coupled tothe electrode and the nerve pressure device, the medical devicecomprising: a controller; an electrical signal generator configured toapply the electrical signal to the first location of the cranial nerve,the peripheral nerve, or the spinal root using the electrode to activateat least the second nerve fiber type at the first location to conducttowards the second location and towards a target innervated structure orsystem; and a pressure signal generator configured to apply the firstpressure to the second location of the cranial nerve, the peripheralnerve, or the spinal root using the nerve pressure device, the firstpressure attenuating conduction of the first nerve fiber type so that ahigher fraction of the second nerve fiber type relative to the firstnerve fiber type conduct away from the second location towards thetarget innervated structure or system.
 16. The medical device system ofclaim 15, further comprising: a sensor to receive at least one body datastream; wherein the electrical signal generator is adapted to apply theelectrical signal to the first location of the cranial nerve, theperipheral nerve or the spinal root based upon the at least one bodydata stream.
 17. The medical device system of claim 16, wherein thesecond location is proximal to the heart, relative to the firstlocation, and the electrical signal is applied as a therapy for acardio-vascular condition.
 18. The medical device system of claim 17,wherein the at least one body data stream comprises sensed body data ofat least one of the following: EKG, blood pressure, respirations, skinresistance, catecholamine concentrations, concentrations of metabolitesof catecholamines, autonomic signals, metabolic signals, glucose levels,or lactic acid concentrations.
 19. The medical device system of claim15, wherein at least one parameter defining the electrical signal isprogrammably selected, the at least one parameter selected from a pulsecurrent, a pulse width, a frequency, an on-time and an off-time.
 20. Themedical device system of claim 15, wherein the nerve pressure device iscapable of applying a plurality of pressures at the second location,wherein the pressure signal generator is capable of applying theplurality of pressures to the second location using the nerve pressuredevice, and wherein the plurality of pressures are selectable.